title: Computational approach to de novo discovery of fragment binding for novel protein states.
abstract: In silico fragment-based drug discovery has become an integral component of the new fragment-based approach that has evolved over the past decade. Protein structure of high quality is essential in carrying out computational designs, and protein flexibility has been shown to impact prospective designs or docking experiments. Here we introduce methodology to calculate protein normal modes and protein molecular dynamics in torsion space which enable the development of multiple protein states to address the natural flexibility of proteins. We also present two fragment-based sampling methods, grand canonical Monte Carlo and systematic sampling, which are used to study protein-fragment interactions by generating fragment ensembles and we discuss the process by which these ensembles are linked to design ligands.
authors.affiliation: Department of Design, Ansaris, Four Valley Square, Blue Bell, Pennsylvania, USA.
authors.forename: Zenon D
authors.initials: ZD
authors.lastname: Konteatis
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Klon
authors.forename: Jinming
authors.initials: J
authors.lastname: Zou
authors.forename: Siavash
authors.initials: S
authors.lastname: Meshkat
mesh_terms: D000465:Algorithms; D000495:Allosteric Site; D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D054852:Small Molecule Libraries; D013816:Thermodynamics; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry
chemical_list: D011506:Proteins; D054852:Small Molecule Libraries; D011494:Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases